Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2191861 | Journal of Molecular and Cellular Cardiology | 2007 | 10 Pages |
Reduced function of the cardiac ryanodine receptor or calsequestrin causes catecholaminergic ventricular tachycardia (VT). These proteins regulate sarcoplasmic Ca2+ release in close conjunction with two accessory proteins, triadin and junctin. Based on data from cardiomyocytes, we hypothesized that enhanced triadin expression could cause VT. We assessed arrhythmias and electrophysiological changes in vivo and in the beating heart in mice expressing junctin, triadin, or both proteins (TRD×JCN), and measured calcium transients in isolated ventricular cardiomyocytes. TRD×JCN mice were studied to compensate the down-regulation of junctin expression in triadin-expressing mice. Exercise or stress provoked repetitive VT in freely roaming TRD×JCN mice whenever heart rate increased above approximately 600 bpm (p < 0.05 vs. the three other genotypes). TRD×JCN mice expressed total triadin 2.9-fold (p < 0.05) and total junctin not different to wildtype (p = ns). Left ventricular systolic function was not different between lineages. β-adrenoreceptor stimulation (orciprenaline 1.7 μM) provoked early-coupled ventricular ectopy and repetitive VT in isolated, Langendorff-perfused TRD×JCN hearts (p < 0.05). Under conditions associated with VT (high pacing rate, catecholamine stimulation), action potential duration was shorter in TRD×JCN with VT than in the other genotypes and shorter than in TRD×JCN hearts without VT (p < 0.05). Ca2+ transient duration was prolonged in Indo1-loaded TRD×JCN cardiomyocytes under VT-provoking conditions. Action potential prolongation by mexiletine (2 μM or 4 μM) or clarithromycine (150 μM) suppressed VT. Expression of triadin provokes stress- and tachycardia-related ventricular arrhythmias in mice. An imbalance between prolonged intracellular calcium release and shortening of the ventricular action potential may contribute to genesis of arrhythmias in this model.